Down syndrome (DS) or trisomy 21 is the most common autosomal chromosome abnormality and the most common genetic predisposing factor for acute leukemia (est. incidence 0.5-2%). More commonly, DS infants may also exhibit a monoclonal spontaneously remitting transient myeloproliferative disorder (TMD) that is associated with a 20-30% risk for subsequent leukemia. Little is understood regarding the predisposition to TMD or leukemia in children with DS, or the basis for the progression of some but not all TMD cases into leukemia. This study is a correlative biological study of the national Children's Oncology Group clinical therapy trial COG-A2971 that enrolled and collected serial bone marrow and blood specimens from children with Down syndrome and TMD or acute myeloid leukemia (AML). It is our overall hypothesis that we will be able to identify biomarkers of susceptibility and progression that identify patients at risk of developing leukemia. In this study we will: (1) investigate the molecular features of TMD and follow the molecular changes that accompany resolution of TMD or progression to leukemia; (2) investigate pharmacogenetic modifiers of therapy outcome in children with AML and DS and compare the results with those seen in children with AML without DS, and (3) study potential genetic modifiers of susceptibility to leukemia in children with DS and compare them with modifiers of susceptibility in children with AML without DS. These studies may in the future form the basis of improved medical surveillance regimens, and as a long-term objective, help to develop the infrastructure for the study of nontoxic chemopreventive agents to decrease risk for development of leukemia in this population. [unreadable] [unreadable]